The majority of early-onset familial Alzheimer disease (AD) cases are caused by mutations in the highly related genes presenilin-1 (PS1) and presenilin-2 (PS1) and presinilin-2 (PS2) which encode what are predicted to be integral membrane proteins with six or eight membrane spanning domains. Because the presenilin mutations account for the majority of cases of inherited early onset forms of AD, understanding the normal function of the presenilins and how mutations in these proteins lead to Alzheimer disease are central questions in Alzheimer's research. In terms of AD, two aspects of presinilin activity have received particular attention. First, mutant presenilin has been shown to alter the relative levels of the longer and potentially more pathogenic amyloid Abeta peptide variants (i.e., Abeta1-42/43). Second, mutant presenilin has been shown to promote apoptosis. With regard to the role of presenilins in apoptosis, there is evidence suggesting that a protein-protein interaction between the COOH-terminus of PS2 and as yet unidentified protein(s) is responsible for activation for apoptosis. This proposal focuses on identifying and characterizing protein(s) which interacts with the COOH- terminus of the presenilins, mediating their effects on apoptosis and, possibly, on altering the relative levels of the longer Abeta variants. The specific aims are as follows: 1) To identify and characterize proteins that interact with the COOH-terminus of the presenilins; 2) To study the role of interactor protein(s) in presenilin-mediated apoptosis; 3) To dissect the role of interactor protein(s) in presenilin-mediated increases in longer Abeta variants; and, 4) To elucidate the relationship between presinilin-mediated apoptosis and presenilin-mediated increases in longer Abeta variants.